8-K

 

 

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

 

 

FORM 8-K

 

 

CURRENT REPORT

Pursuant to Section 13 or 15(d)

of the Securities Exchange Act of 1934

Date of Report (Date of Earliest Event Reported): January 22, 2020

 

 

Proteostasis Therapeutics, Inc.

(Exact name of registrant as specified in its charter)

 

 

 

Delaware   001-37695   20-8436652

(State or other jurisdiction

of incorporation)

 

(Commission

File Number)

 

(I.R.S. Employer

Identification No.)

 

80 Guest Street, Suite 500

Boston, MA

  02135
(Address of principal executive offices)   (Zip Code)

Registrant’s telephone number, including area code (617) 225-0096

(Former name or former address, if changed since last report)

 

 

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:

 

Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

 

Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

 

Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

 

Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Securities registered pursuant to Section 12(b) of the Act:

 

Title of each class

 

Trading

Symbol(s)

 

Name of each exchange

on which registered

Common stock, par value $0.001 per share   PTI   The Nasdaq Global Market

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).

Emerging growth company  ☒

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.  ☒

 

 

 


Item 7.01

Regulation FD Disclosure.

On January 22, 2020, the Company issued the press release attached hereto as Exhibit 99.1.

The furnishing of the attached press release is not an admission as to the materiality of any information therein. The information contained in the press release is summary information that is intended to be considered in the context of more complete information included in the Company’s filings with the U.S. Securities and Exchange Commission, or the SEC, and other public announcements that the Company has made and may make from time to time by press release or otherwise. The Company undertakes no duty or obligation to update or revise the information contained in this report, although it may do so from time to time as its management believes is appropriate. Any such updating may be made through the filing of other reports or documents with the SEC, through press releases or through other public disclosures. For important information about forward looking statements, see the “Safe Harbor” section of the press release in Exhibit 99.1 attached hereto.

The information in this Item 7.01 of this Current Report on Form 8-K and Exhibit 99.1 attached hereto shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, or otherwise subject to the liabilities of that section or Sections 11 and 12(a)(2) of the Securities Act of 1933, as amended. The information contained in this Item 7.01 and in the press release attached as Exhibit 99.1 to this Current Report shall not be incorporated by reference into any filing with the SEC made by the Company, whether made before or after the date hereof, regardless of any general incorporation language in such filing, except as expressly set forth by specific reference in such filing.

 

Item 8.01

Other Events.

On January 22, 2020 the Company posted an updated corporate presentation to its website www.proteostasis.com. A copy of the presentation is filed herewith as Exhibit 99.2 and is incorporated herein by reference.

 

Item 9.01

Financial Statements and Exhibits.

(d) Exhibits.

 

Exhibit
No.

  

Description

99.1    Press Release, furnished herewith.
99.2    Corporate Presentation, filed herewith.


EXHIBIT INDEX

 

Exhibit
No.

  

Exhibit Name

99.1    Press Release, furnished herewith.
99.2    Corporate Presentation, filed herewith.


SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

 

Date: January 22, 2020     PROTEOSTASIS THERAPEUTICS, INC.
    By:  

/s/ Meenu Chhabra

      Meenu Chhabra
      President and Chief Executive Officer
EX-99.1

Exhibit 99.1

 

LOGO

Proteostasis Therapeutics Announces Keystone Symposia Presentation of

Organoid Study from More than 300 Adult CF Patients

Ex vivo Data with Proteostasis’ CFTR Modulators in non-F508del and non-G551D CF Genotypes Marks First Step Toward a Personalized Medicine Approach

BOSTON, Mass. – January 22, 2020 – Proteostasis Therapeutics, Inc. (NASDAQ:PTI), a clinical stage biopharmaceutical company dedicated to the discovery and development of groundbreaking therapies to treat cystic fibrosis (CF) and other diseases caused by dysfunctional protein processing, today announced the presentation of results from an ex vivo study of the Company’s proprietary cystic fibrosis transmembrane conductance regulator (CFTR) modulators in organoids from individuals with CF who are ineligible for the current standard of care CFTR modulator therapies due to their genotype, a population of approximately 2,300 adults in Europe alone. The results, outlined in a poster entitled “Intestinal Organoid Models as a Path for Personalized Therapy Development in Cystic Fibrosis,” will be presented at the Keystone Symposia on Tissue Organoids taking place on January 19-23, 2020 in Vancouver, BC, Canada.

The study remains on track for collecting tissue samples from up to 500 CF patients with less common genotypes by the end of Q1 2020 for assaying as organoids and for testing responsiveness to investigational CFTR modulators, including Proteostasis’ CFTR potentiator, corrector and amplifier, dirocaftor (DIR), posenacaftor (POS) and nesolicaftor (NES), respectively. Data from the organoid study will be used to select a subset of patients for a confirmatory clinical trial, known as the CHOICES trial (Crossover trial based on Human Organoid Individual response in CF - Efficacy Study). This organoid program is a strategic initiative funded by the European Commission, which has invited a select number of drug developers and leading researchers in CF to build a roadmap for personalized therapeutics in CF. Based on the outcome of the study, this transition from precision to personalized medicine for the treatment of CF could begin in patients with less common mutations.

The organoid study seeks to measure the ex vivo responsiveness to the PTI CFTR modulators in tissue samples collected via a rectal suction procedure. The rectal tissue is developed into an organoid or a miniaturized organ that is genetically identical to the patient donor and shares the same micro-anatomy as the organ from which they were derived. Organoid cultures from more than 370 adult CF patients have been established to date. Based on initial genotype analysis, approximately 85% of enrolled patients carry genotypes that lead to CFTR protein synthesis making them eligible for ex vivo study with DIR, POS and NES. Data from the organoid study will be used to select a subset of patients for the confirmatory CHOICES clinical trial. The poster outlining these results is available on the Company’s website at proteostasis.com.

“With advancements in models such as organoid testing used to predict the effectiveness of CFTR modulator treatments, the transition from precision to personalized medicine in this disease is an inevitability,” said Geoffrey Gilmartin, M.D., M.M.Sc., Chief Medical Officer of Proteostasis Therapeutics. “Essential to this transition is the introduction of more therapeutic options that expand the treatment choices for patients and physicians. As the only company in the HIT-CF consortium with a proprietary combination of novel CFTR modulators that have demonstrated positive Phase 2 data, we remain very enthusiastic about its progress and the translation of these results to the clinic in the CHOICES trial.”

“Access to CFTR modulators in Europe is challenged by either the ineligibility of patients for approved drugs due to their genotype, or by the lack of reimbursement for approved drugs due to their high cost,” said Cornelis K. van der Ent, Professor at the Department of Pediatric Pulmonology of the Wilhelmina


LOGO

 

Children’s Hospital at the University Medical Center in Utrecht, the Netherlands and HIT CF Project Coordinator. “An organoid-assay-based personalized medicine approach offers the potential of a new decision-supporting technology to inform clinical decisions and provide each patient with CFTR modulators that lead to their highest possible benefit.”

CHOICES, which is expected to initiate in mid-2020, will be the first ever personalized medicine-based study in CF. Fully funded by the HIT-CF, this trial is a placebo controlled, double blind, crossover study with an 8-week treatment period and 6 months of uninterrupted dosing. The CHOICES trial will complement the MORE trial (Modulator Options to RestorE CFTR study), a global, Phase 3, randomized, placebo-controlled study in CF subjects with the common F508del homozygous mutation, which is designed to confirm the positive efficacy and tolerability results from a recently completed Phase 2 study of the Proteostasis CFTR modulator triple combination.

About HIT-CF Europe

HIT-CF Europe is a research project which aims to provide better treatment and better lives for people with cystic fibrosis (CF) and rare mutations. To achieve this, drug candidates are first tested on patient-derived organoids in qualified laboratories across Europe. Subsequently, based on the measured signal in the organoids, a smaller group of patients will be invited to participate in a clinical trial. All participating centers are part of the European Cystic Fibrosis Society – Clinical Trial Network (ECFS-CTN). The project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 755021. For more information, visit www.hitcf.org.

About Proteostasis Therapeutics, Inc.

Proteostasis Therapeutics, Inc. is a clinical stage biopharmaceutical company developing small molecule therapeutics to treat cystic fibrosis and other diseases caused by dysfunctional protein processing. Headquartered in Boston, MA, the Proteostasis Therapeutics team focuses on identifying therapies that restore protein function. For more information, visit www.proteostasis.com.

Safe Harbor

To the extent that statements in this release are not historical facts, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Words such as “aim,” “may,” “will,” “expect,” “anticipate,” “estimate,” “intend,” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. Examples of forward-looking statements made in this release include, without limitation, statements regarding the potential of our proprietary combination therapies for the treatment of CF, the potential benefit to patients of our proprietary combination therapies, expected timing of patient enrollment in our clinical studies and cohorts for our clinical programs, including our planned Phase 3 programs and initiation of registrational or pivotal studies. Forward-looking statements made in this release involve substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by the forward-looking statements, and we, therefore cannot assure you that our plans, intentions, expectations or strategies will be attained or achieved. Such risks and uncertainties include, without limitation, the possibility final or future results from our drug candidate trials (including, without limitation, longer duration studies) do not achieve positive results or are materially and negatively different from or not indicative of the preliminary results reported by the Company (noting that these results are based on a small number of patients and small data set), uncertainties inherent in the execution and completion of clinical trials (including, without limitation, the possibility that FDA or other regulatory agency comments delay, change or do not permit trial commencement, or intended label, or the FDA or other

 


LOGO

 

regulatory agency requires us to run cohorts sequentially or conduct additional cohorts or pre-clinical or clinical studies), in the enrollment of CF patients in our clinical trials in a competitive clinical environment, in the timing of availability of trial data, in the results of the clinical trials, in possible adverse events from our trials, in the actions of regulatory agencies, in the endorsement, if any, by therapeutic development arms of CF patient advocacy groups (and the maintenance thereof), and those set forth in our Annual Report on Form 10-K for the year ended December 31, 2018, our Quarterly Report on Form 10-Q for the quarter ended September 30, 2019 and our other SEC filings. We assume no obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

CONTACTS:

Investors:

David Pitts / Claudia Styslinger

Argot Partners

212.600.1902

david@argotpartners.com / claudia@argotpartners.com

Media:

David Rosen

Argot Partners

212.600.1902

david.rosen@argotpartners.com

 

EX-99.2

Slide 1

MORE CHOICES IN CYSTIC FIBROSIS TREATMENT: NOVEL CFTR MODULATOR COMBINATIONS #CForward Corporate Presentation January 2020 Exhibit 99.2


Slide 2

Safe Harbor and Disclaimer To the extent that statements in this presentation are not historical facts, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Words such as “aim,” “may,” “will,” “expect,” “anticipate,” “estimate,” “intend,” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements.  Examples of forward-looking statements made in this presentation include, without limitation, statements regarding the potential of our proprietary combination therapies for the treatment of CF, the potential benefit to patients, including those with extremely rare genotypes, of our proprietary combination therapies, the expected timing of the initiation of, patient enrollment in, data from, and our completion of, our clinical studies and cohorts for nesolicaftor (PTI-428), posenacaftor (PTI-801), dirocaftor (PTI-808) and our combination therapy candidates, cash guidance, and HIT CF consortium subject recruitment, and in vitro testing and conduct of clinical trials with our drug candidates.  Forward-looking statements made in this presentation involve substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by the forward-looking statements, and we therefore cannot assure you that our plans, intentions, expectations or strategies will be attained or achieved. Such risks and uncertainties include, without limitation, the possibility that final or future results from our drug candidate trials (including, without limitation, longer duration studies) do not achieve positive results or are materially and negatively different from or not indicative of the preliminary results reported in this presentation (noting that these results are on a small number of patients and small data set), uncertainties inherent in the execution and completion of clinical trials (including, without limitation, the possibility FDA requires us to run cohorts sequentially or conduct additional cohorts or pre-clinical or clinical studies), in the enrollment of CF patients in our clinical trials, in the timing of availability of trial data, in the results of the clinical trials, in possible adverse events from our trials, in the actions of regulatory agencies, in endorsement, if any, by CF patient advocacy groups, the potential activity of our drug candidates in organoids and in personalized clinical trials in extremely rare genetic mutations may not be realized, and those set forth in our Annual Report on Form 10-K for the year ended December 31, 2018, our Quarterly Report on Form 10-Q for the period ended September 30, 2019, and our other SEC filings. We assume no obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.   This presentation also contains estimates and other statistical data made by independent parties and by us relating to, among other items, disease incidence, market size and other data about our industry.  This data involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. Projections, assumptions and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of risk and uncertainty.  New risks emerge from time to time, and neither we nor any other person makes any representation as to the accuracy or completeness of such data or undertakes any obligation to update such data after the date of this presentation. By attending, viewing, or receiving this presentation you acknowledge you are solely responsible for your own assessment of the market and our market position and that you will conduct your own analysis and are solely responsible for forming your own view of the potential future performance of our business. The trademarks included in this presentation are the property of the owners thereof and are used for reference purposes only.  Such use should not be construed as an endorsement of the Company or its securities.


Slide 3

Highlights 2019 3 3 novel CFTR modulators ready for registrational studies in 2020 Proof-of-concept established across 14 clinical studies spanning 9 countries with over 300 subjects dosed Proprietary potentiator/corrector/amplifier combination of DIR/POS/NESa delivers ppFEV1 improvement of +8 ppFEV1 compared to placebo in F508del homozygous patients. $77.8M at the end of Q3; sufficient to fund operations and Phase 3 programs into 2021 Financially solid Phase 3 Planning Underway (MORE Trial, CHOICES Trial) Based on Positive Phase 2 Data On track to initiate registrational studies in CF subjects with both common (MORE) and rare genotypes (CHOICES) 28 day clinical Phase 2 data is consistent with predicted benefit based on independent in vitro testing performed by the Cystic Fibrosis Foundation in HBE cells from individuals with CF Phase 2 dose range finding complete aDIR – dirocaftor; POS – posenacaftor; NES – nesolicaftor; ELX – elexacaftor; TEZ – tezacaftor; IVA – ivacaftor


Slide 4

New Options for CFTR Modulators are Needed 4 aTRIKAFTA Phase 3 Trial; Heijerman et al, Lancet, 2019, not part of a head-to-head study; change with TEZ/IVA alone not reported PE – pulmonary exacerbation; n/a – not available LS Mean Treatment Difference in ppFEV1 (Mean Percentage Points, 95% CI, p-value) Treatment Effect by Age, Baseline ppFEV1, PE Burden and Prior Modulator Use Subjects 18 years and above Subjects with <70 ppFEV1 at baseline Subjects with at least 2 PEs within 12 months prior to study Subjects with prior CFTR modulator use ELX/TEZ/IVA vs. TEZ/IVAa n=53 +8 (6, 11) (n=38) +11 (8, 14) (n=35) n/a +8 (5, 11) (n=31) In a Phase 3 study, ELX/TEZ/IVA in F508del homozygous patients delivered a wide range of lung function response (-2.5 to +20 ppFEV1); ~ 1 in 3 subjects fall below 5 ppFEV1 improvement; ~ 2 out of 3 subjects fall below 10 ppFEV1a AURORA Phase 3 Trial Heijerman et al. Cystic Fibrosis (CF) is a life limiting genetic disease with approximately 48,000 patients in Europe and ~ 30,000 in the US - Only ~ 2 out of 5 of the ~48,000 people with CF in Europe have access to any CFTR modulators


Slide 5

5 AUG 2012 FIRST HIGH THROUGHPUT SCREEN JUN 2016 FIRST HEALTHY VOLUNTEER DOSED JUL 2016 FIRST PERSON WITH CF DOSED APR 2017 SECOND IND (CORRECTOR POSENACAFTOR) JUL 2017 THIRD IND (POTENTIATOR DIROCAFTOR) JUN 2018 START OF TRIPLE COMBO PHASE 1 JAN 2018 START OF DOUBLE COMBO PHASE 1 JUL 2019 START OF DOUBLE AND TRIPLE COMBO PHASE 2 JAN 2016 FIRST IND (AMPLIFIER NESOLICAFTOR) OVER 300 PEOPLE WITH CF DOSED 14 DIFFERENT CLINICAL STUDIES 9 DIFFERENT COUNTRIES Proteostasis Therapeutics Clinical Development Journey


Slide 6

Amplifier NESOLICAFTOR { { Corrector POSENACAFTOR Potentiator DIROCAFTOR { More Choices for Restoration of CFTR Activity Dirocaftor (PTI-808 or DIR) Fast Track (FDA) Posenacaftor (PTI-801 or POS) Fast Track (FDA) Nesolicaftor (PTI-428 or NES) Breakthrough Therapy (FDA) Orphan Drug (EMA) Fast Track (FDA) 6 Proteostasis Therapeutics (PTI) drug candidates have received designations from US and EU regulatory agencies:


Slide 7

Phase 2 Study Design Not currently taking CFTR modulator therapies Safety and tolerability of dose combinations of DIR/POS/NES Change in ppFEV1 CF subjects homozygous or heterozygous for the F508del mutation ≥18 years of age Lung function ≥40 to ≤90 (ppFEV1) Excluded subjects: colonized with organisms associated with a more rapid decline in pulmonary status with respiratory instability within 28 days of first dose Study Eligibility Primary Study Objectives Secondary Study Objectives PK profiles of dose combinations of DIR/POS/NES Change in sweat chloride concentration Follow-Up Screening Period 300 mg DIR / 600 mg POS 300 mg DIR / 600 mg POS / 10 mg NES placebo 28 days 4 weeks 14 days Randomization (2:2:1) Treatment Period 7 Sweat chloride concentration above 60 mmol/L ClinicalTrials.gov identifier: NCT03251092


Slide 8

F508del Homozygous F508del Heterozygous Pooled Placebo DIR/POS n=11 DIR/POS/NES n=11 DIR/POS n=16 DIR/POS/NES n=16 - n=14 Age; years (mean, SD) 30.8 (9.2) 30.1 (6.3) 26.7 (7.0) 27.6 (6.4) 35.6 (13.9) Male sex (n, %) 10 (91) 3 (27) 7 (44) 9 (56) 8 (57) Percentage of predicted FEV1 (mean, SD) 52.5 (13.7) 57.6 (11.0) 66.5 (13.6) 56.0 (12.8) 57.2 (12.7) Sweat chloride concentration; mmol/L (mean, SD) 97.6 (5.4) 100.1 (8.7) 97.8 (8.8) 100.2 (7.4) 99.5 (10.3) BMI; kg/m2 (mean, SD) 22.6 (3.8) 22.6 (2.7) 21.9 (2.9) 22.8 (2.6) 22.0 (1.9) Weight; kg (mean, SD) 67.4 (12.0) 63.1 (8.8) 60.3 (9.7) 64.7 (12.0) 62.8 (7.9) Baseline Demographics and Clinical Characteristics of F508del Homozygous and Heterozygous Study Cohorts 8


Slide 9

F508del Homozygous F508del Heterozygous Pooled Placebo DIR/POS n=11 DIR/POS/NES n=11 DIR/POS n=16 DIR/POS/NES n=16 - n=14 Any adverse event (AE) (n, %) 9 (81.8) 9 (81.8) 13 (81.3) 12 (75.0) 13 (92.9) Respiratory-related AEs (occuring in >2 subjects total) Cough (n, %) Sputum increased (n, %) Oropharyngeal pain (n, %) 1 (9.1) 1 (9.1) 1 (9.1) 2 (18.2) 1 (9.1) 1 (9.1) 2 (12.5) 1 (6.3) 1 (6.3) 1 (6.3) 3 (18.8) 0 (0.0) 3 (21.4) 1 ( 7.1) 1 (7.1) Most common AEs Pulmonary exacerbation (n, %) Headache (n, %) 1 (9.1) 0 (0.0) 2 (18.2) 0 (0.0) 3 (18.8) 2 (12.5) 3 (18.8) 1 (6.3) 3 (21.4) 6 (42.9) Drug Combinations in F508del Homozygous and Heterozygous Study Subjects were Generally Well Tolerated 9 No clinically important trends in chemistry, hematology, vital signs or ECG were observed


Slide 10

10 Targeted Exposures of DIR/POS/NES Achieved PK parameters of each study drug were as expected based on the data from the previously reported studies in subjects with CF Mean Cmin concentrations at steady state for DIR/POS exceeded their corresponding in vitro EC90 values PK parameters for DIR/POS were consistent across subjects receiving DIR/POS/NES and subjects receiving DIR/POS in each cohort, indicating DIR/POS PK is not affected by coadministration with NES PK parameters for each study drug were consistent in F508del homozygous and heterozygous subjects, suggesting CFTR genotype does not have an impact on PK of any of the study drugs Mean Cmin concentration at steady state for NES achieved its targeted in vitro EC10 value


Slide 11

Absolute Improvement in ppFEV1 Achieved with DIR/POS/NES in F508del Homozygous Subjects 11 ppFEV1 Lung Function Pooled placebo (n=14) DIR/POS/NES (n=11) bTotal ITT population; number of subjects with non-missing measurements at week 4; PBO – placebo; PE – pulmonary exacerbation; n/a – not available LS Mean Treatment Difference in ppFEV1 (Mean Percentage Points, 95% CI, p-value) PTI Phase 2 Trial Treatment Effect by Age, Baseline ppFEV1 PE Burden and Prior Modulator Use DIR/POS/NES vs. PBO n=11b Subjects 18 years and above +8 (3, 12) p ≤ 0.01 (n=11) Subjects with <70 ppFEV1 at baseline +10 (5, 14) p ≤ 0.001 (n=9) Subjects with at least 2 PEs within 12 months prior to study +12 (4, 19) p ≤ 0.01 (n=5) Subjects with prior CFTR modulator use +12 (6, 18) p ≤ 0.001 (n=7)


Slide 12

Absolute Improvement in Sweat Chloride Achieved with DIR/POS/NES in F508del Homozygous Subjects 12 Sweat Chloride Sweat chloride is reduced by -29 mmol/L (95% CI; -42, -16) (p < 0.0005) compared to pooled placebo pooled placebo (n=13) DIR/POS/NES (n=11) Number of subjects with non-missing measurements Absolute Change from Baseline in Sweat Chloride Concentration Through Week 4 (mmol/L)


Slide 13

Absolute Improvement in ppFEV1 with DIR/POS/NES is Greater than DIR/POS in F508del Homozygous Subjects 13 CFTR Modulator Combinations by Age, PE Burden and Prior Modulator Use DIR/POS n=11 DIR/POS/NES n=11 Subjects 18 years and above +3 (-2, 7) ns (n=10)a +8 (3, 12) p ≤ 0.01 (n=11) Subjects with <70 ppFEV1 at baseline +4 (-1, 9) ns (n=9) +10 (5, 14) p ≤ 0.001 (n=9) Subjects with at least 2 PEs within 12 months prior to study +7 (-1, 15) ns (n=6) +12 (4, 19) p ≤ 0.01 (n=5) Subjects with prior CFTR modulator use (TEZ/IVA and/or LUM/IVA poor responders)b +5 (-1, 10) ns (n=5) +12 (6, 18) p ≤ 0.001 (n=7) ppFEV1 Lung Function pooled placebo (n=14) DIR/POS (n=11) aTotal ITT population; number of subjects with non-missing measurements at week 4 b DIR/POS +6 ppFEV1 vs. baseline at week 4 with no prior CFTR modulator use; ns – not significant; PE – pulmonary exacerbation; n/a – not available LS Mean Treatment Difference in ppFEV1 (Mean Percentage Points, 95% CI, p-value)


Slide 14

Absolute Improvement in Sweat Chloride Achieved with DIR/POS in F508del Homozygous Subjects pooled placebo (n=13) DIR/POS (n=11) 14 Sweat chloride is reduced by -15 mmol/L (95% CI; -24, -6) (p < 0.01) compared to pooled placebo Sweat Chloride Absolute Change from Baseline in Sweat Chloride Concentration Through Week 4 (mmol/L) Number of subjects with non-missing measurements


Slide 15

Initial Evidence that DIR/POS/NES Has Biological Activity Beyond the F508del Homozygous Genotype Responder rate (> ppFEV1 improvement of 5 percentage points or more) was 3x as high in subjects who received active (23%) vs. placebo (7%). Mean changes in ppFEV1 were not statistically significant Absolute Change from Baseline in Sweat Chloride Concentration Through Week 4 (mmol/L) in F508del heterozygous population Changes in sweat chloride concentration were statistically significant (p<0.01, p<0.0001) 15 First clinical study in F508del heterozygous population Subjects on active treatment experienced a range of responses from -13 to +20 in ppFEV1 and from +12 mmol/L to -79 mmol/L in sweat chloride concentration Broad range of responses observed is consistent with CFTR modulators mechanism of action 40 subjects with at least 26 different genotypes enrolled into F508del heterozygous cohort


Slide 16

16 www.hitcf.org PTI and HIT-CF Partnered to Develop DIR/POS/NES Initially Targeting up to 2,300 Adult Patients in Europe Ex vivo organoid testing Magnitude of organoid swelling will inform responders vs. non-responders Responders and non-responder will be invited to a clinical trial CTN centers collect rectal biopsies RESPONDER NON RESPONDER ~300 patients recruited by Dec 2019 Total target 500 patients by H1 2020 ~Ongoing Ex Vivo Study in Patient Derived Organoids to Identify Responders to PTI Combinations ~H1 2020 Patient Recruitment into CHOICES Study ~Mid 2020 Initiation of CHOICES Study in CTN centers (58 sites in 17 countries by 2020)


Slide 17

All patients meet the inclusion and exclusion criteria for the subsequent clinical trial Country # Patients Israel 28 Czech Republic 10 The Netherlands and Germany 81 Belgium 30 Sweden 21 Italy 84 Poland 8 England 26 Spain 26 Denmark 4 France 11 Total included as of December 2019 329 ~85% of enrolled patients carry genotypes that lead to CFTR protein synthesis making them eligible for the ex vivo study with DIR, POS and NES 17 Genotypes by CFTR Mutation Type Enrolled in HIT-CF ~500 Patients Projected to Complete Enrollment in Q1 2020, Ongoing Ex Vivo Study with PTI Compounds


Slide 18

THANK YOU #CForward “Proteostasis is striving to shake up the CF community in ways better than the vest ever could.” Brad Dell, a person with CF